The present invention relates generally to the treatment of cardiovascular disease. More specifically, the present invention relates to treatment of atherosclerosis.
Cardiovascular disease is the leading cause of death in the United States. In the United States, of a population of 226.5 million in 1980, 551,400 died of ischemic heart disease and 169,500 died of cerebrovascular causes related to arterial disease. See, Merck Manual, Fifteenth Edition, pp. 386.
Atherosclerosis is a form of arteriosclerosis marked by the formation of atheromas. The disease causes the lumen of an artery to become narrowed or blocked (occluded). The atheroma obstructs circulation by protruding into the arterial lumen. The narrowing of the artery restricts blood flow to the organ that is nourished by the artery. The reduced blood flow results in the deterioration of the organ to the point wherein the organ can be permanently damaged unless the blockage of blood flow is removed. When an artery that serves the heart is narrowed or blocked, this pathological process results in a heart attack.
The relationship between hypercholesterolemia, abnormal lipoprotein profiles, and atherogenesis has been well defined. More recently, oxidative modification of lipoproteins, lipoprotein (a), and induction of cytokines and growth factors have been implicated as important factors in the initiation and progression of atherosclerotic plaques.
Lipid peroxidation is one of the deleterious effects of oxidative stress. Peroxidation of the unsaturated lipid moieties of lipoproteins results in a sequelae of events yielding oxidatively modified lipoproteins and macrophage derived foam cells. These cells, which constitute a significant portion of the cells within atherosclerotic lesions, phagocytose and degrade oxidatively modified lipoproteins. See, Rosenfeld et al., Macrophage-derived Foam Cells Freshly Isolated from Rabbit Atherosclerotic Lesions Degrade Modified Lipoproteins, Promote Oxidation of Low-Density Lipoproteins, and Contain Oxidation-specific Lipid-Protein Adducts, J. Clin. Invest., Vol. 87, pp. 90-99 (1991).
A number of pharmaceutical interventions have been proposed for treating and/or preventing atherosclerosis. Although the logic of attempting to protect against lipoprotein modification and ensuing lipid hydroperoxide generation may be apparent, the role of glutathione as providing antioxidant protection is at best unsettled. Heinecke et al., The Role of Sulfur-containing Amino Acids in Superoxide Production and Modification of Low Density Lipoprotein by Arterial Smooth Muscle Cells. J. Biol. Chem., Vol. 262, pp. 10098-10103, 1987, reported that monkey arterial smooth muscle cells produce reactive oxygen species and modify low density lipoprotein by an L-cysteine dependent process. This effect was postulated to involve the production of reduced thiols from the cystine, followed by thiol mediated modification of the lipoprotein.
Parthasarathy, Oxidation of Low-density Lipoprotein by Thiol Compounds Leads to its Recognition by the Acetyl LDL Receptor, Biochim. et Biophys. Acta, Vol. 917, pp. 337-340, 1987 also demonstrated that reduced glutathione and other compounds with reduced thiols promote the oxidation of LDL in the absence of cells. This reaction was hypothesized to be the result of thiol reaction with redox metals, generating free radicals which promote modification of LDL. Parthasarathy further notes: "There appears to be some correlation among plasma cholesterol levels, incidence of atherosclerosis, and levels of protein-bound-homocysteine. Cysteine and other thiols, including protein-bound thiols, undergo auto-oxidation in the presence of redox metals, generating peroxide, superoxide anion and hydroxy radicals in addition to thiol-derived free radicals." See pp. 339.
In many cases of atherosclerosis, invasive procedures such as bypass surgery or angioplasty are required to reestablish an occluded lumen to proper diameter.
Due to its intrusive nature, bypass surgery inherently has a number of disadvantages. Accordingly, the popularity of angioplasties has increased dramatically. In the United States in 1989, hundreds of thousands of angioplasties were performed. This number is rapidly increasing. Fortunately, for many patients, angioplasty permanently reopens the previously occluded arteries. However, in approximately 30% of the occluded arteries which are opened by an angioplasty technique, the arteries re-occlude within six months of the procedure. This results in symptoms of cardiac ischemia, such as chest pain, exercise intolerance, and shortness of breath. The patient's risk of disabling or fatal heart attack is markedly increased.
It is believed that re-stenosis in a previously treated segment of an artery is due, at least in part, to the stretch-induced damage of arterial tissue. The response to the damage caused by the inflation of a balloon catheter is an exaggerated healing response that includes proliferation of the endothelial cells.
Likewise, even in bypass surgery there is a danger of re-stenosis in the patient. Bypass grafts in 40% of patients restenose within 5 years of the surgical procedure